Chronic Obstructive Pulmonary Disease (COPD) is a chronic ainway infiammatory disease with important systemic manifestations that account for a substantial part of its morbidity and mortality. The identification of systemic biomarkers that can predict inception of this disease may provide important insights into its molecular mechanisms and have critical implications for prevention. Yet, to date studies of biomarkers of COPD have been limited by the use of only a few markers at a time and by the cross-sectional nature of the data, which has precluded any comprehensive and conclusive resolution of biomarkers temporally linked to incidence of COPD. Under NHLBI-funded HL095021, we have recently measured a large panel of 108 analytes in 794 serum samples that were collected at the enrollment survey (1972) of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD), for which extensive phenotypic information on lung function and respiratory health is now available throughout its 24-year follow-up period. These analytes, which represent molecules involved in multiple potential COPD pathways, were measured with a bead-based multi analyte profile approach, which allows optimization of utilization of large epidemiological bio-repositories. In this application, we propose 1) to validate serum biomarker signatures that were identified in TESAOD as predictive of incidence of COPD in the independent cohort of the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA); and 2) to determine whether Integrating information on both initial levels and temporal changes in serum concentrations increases the ability of the above biomarkers to predict risk of COPD. This will result in the most comprehensive prospective serum biomarker study of COPD to date and will lead to the identification of biomarkers and molecular pathways conclusively linked to incidence of COPD. It will also provide the foundations for CADET Stage II, during which we will seek the long-term goals of determining the molecular mechanisms through which these targets and pathways affect COPD risk and to evaluate their potential clinical applications in primary to tertiary prevention of COPD. RELEVANCE (See instructions): Chronic Obstructive Pulmonary Disease (COPD) is a common disease that carries a substantial burden of morbidity and mortality. This study will lead to the identification of molecules linked to the development of COPD and, in turn, may lead to potential clinical applications in primary to tertiary prevention of this disease.